11/01/2017

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Back to dialysis after graft failure:

Transplantectomy or not?

Stop immunosuppression?

Laurent WEEKERS

CHU Sart-Tilman

Layout

• Introduction

• Epidemiology

• A note of caution on causality and bias

• Patient survival after failed KTx

• Immunization after failed transplant

• Immunosuppression

• Transplantectomy

• An integrated approach

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Introduction

The aim of a successful

transplantation:

– To die in one’s bed at

the 85 years of age with

a functioning transplant

– Yet (almost) every study

on transplant outcome

consider return to

dialysis AND death with

a functioning

transplant as the

metrics for failure

Eurotransplant Annual report - 2015

Introduction

Challenges we are faced when dealing with

patients with failed kidney transplant:

1.(When to initiate RRT?)

2.What to do with immunosuppression?

3.To perform a transplantectomy or not?

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Introduction: Guidelines ?

3.13 TREATMENT OF A

FAILED TRANSPLANT

KIDNEY

There are no evidence-based

guidelines on how failed

transplanted kidneys should

be managed. The

management very much

depends on the clinical

situation of the individual

patient.

http://bts.org.uk/…/13_BTS_Failing_Graft.pdf

EPIDEMIOLOGY

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A few figures,…

• Allograft failure is the 5th cause of

admission to RRT

• Patients with a failed kidney transplant

represent 6-7% of patients on RRT

(USRDS data)

• 15% of patients on the waiting lost for KTx

are re-transplant candidates USRDS data

(14% in our center)

Epidemiology in Belgium

Distribution of ESRD patients

between modalities

Recent evolution of treatment

modalities

41 to 43 % of ESRD pts are KTx Rise over 9 years:

• 26% for RRT

• 39% for KTx

https://eservice.chu-tivoli.be/GNFB/PAGE_PRESENTATION_PUBLIC/

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Flow between treatment

modalities

https://eservice.chu-tivoli.be/GNFB/PAGE_PRESENTATION_PUBLIC/

?

28/897 = 3,1%

A WORD OF CAUTIOUS ON

CAUSALITY & BIAS IN

OBSERVATIONAL STUDIES

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Causality ?

Hill’s criteria

Association is not

causality

PATIENT SURVIVAL AFTER

FAILED KTX

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Mortality: Meta-analysis

Annual mortality 1st year

post return to RRT Decline in mortality rate

beyond one year post

RRT initiation

Kabani et al, NDT 2014, pp1778-1786

RR

-

-

-

-

-

-

-

-

0,91

-

-

-

-

-

0,98

-

-

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Mortality • Higher than in the « naïve-

transplant patients » in most

studies

• Essentially in the first year

post RRT initiation

• Causes:

– Infection: 75 % in old studies

=>16-17% in more recent

ones

– Cardio-vascular: 35-45%

recent studies

Gill et al, KI 2007, pp1778-1786

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Mortality: DOPPS analysis Mortality: « Transplant Failure » vs

« Transplant Naïve »

Bias ?

Adjusted for age, sex, race, BMI, time

since initiation of HD or TX failure, 13

summary comorbid conditions, albumin

and catheter use.

Perl et al, NDT 2012, pp 4464-4472

Is there a way to “adjust” for this

residual confounders?

Adjust for “Dialysis vintage” or

“time spent in CKD”

40 years of functional KTx after

living donation

Dan Med J 2014;61(3):A4796

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Key messages about morbi-mortality

associated with failed KTx

• Transition problem

– Accumulating co-morbidity

– Acceptance and preparation issues

• Hope for the best, prepare for the worst (both to

be kept in mind when eGFR < 20 ml/min)

– Pre-emptive re-transplantation often the best option

– Be ready for RRT anyhow

IMMUNIZATION AFTER FAILED

KTX

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Immunization after failed KTx and its

consequences on future transplantation

Percentage of anti-HLA

immunization after various

immunizing events

% of patients transplanted during

follow-up

HLA Class I and/or II HLA Class I and/or II

Tf: transfusion

G: Pregnancy

Tx: transplantation

**

*

Pernin et al, OP-80, SFT Liège 2016

Effect of transplantectomy on

Donor specific immunization

Del Bello et al, CJASN 2012, pp 1310-1319

Scornik at al, Hum Immunol, 2011 pp 398-401 Lachmann et al, NDT 2016 pp 1351-1359

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Key messages about

immunization after failed KTx

• Most studies found a positive

association between

transplantectomy and

development of de novo DSA

• Confounding effect of

immunosuppression

withdrawal difficult to take into

account

• Two theories to explain this

rise in antibodies after

transplantectomy:

– Sponge effect: antibodies are

adsorbed on endothelial class I

antigens

– On going immunization due to

persistence of donor tissue after

kidney removal

• Immunosuppression can

help to prevent antibody

development even after

failed KTx

• Importance of

documenting anti-HLA

antibodies early after

transplantectomy and/or

immunosuppression

withdrawal

IMMUNOSUPPRESIVE

TREATMENT WITHDRAWAL

AFTER FAILED KTX

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To withdraw IS ?

PRO

• Infection risk associated

with IS

• Cardiovascular risk

associated with IS

• Cancer risk associated

with IS

• Metabolic AE associated

with IS

• Reduction of direct cost

CONS

• Residual kidney function

(especially in PD

patients)

• Minimization of

allosensitization

• Prevention of “graft

intolerance syndrome”*

and acute rejection

• Prevention of adrenal

insufficiency

• Prevention of reactivation

of systemic disease (eg.

SLE, vasculitis)

Graft intolerance syndrome

• Low grade fever

• Flu-like symptoms

• Pain in the graft region

• Hematuria

• Tenderness and swelling of KTx

=> In extreme and rare cases can lead to

transplant rupture

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To withdraw IS ?

“Immunosuppression should be

stopped in patients with renal allograft

failure” Smak Gregoor Clin Transplant 2001

Groupe A: 192 patients on IS

Groupe B: 90 patients off IS

“Continued transplant

immunosuppression may prolong

survival after return to peritoneal

dialysis” Jassal AJKD 2002

• Decision analytic model

• �2 assumptions:

survival benefit of better

GFR naïve Tx = failed KTx

risks of carcinoma and

opportunistic infection failed

KTx after IS w/d = general

pop w/o IS

• Life expectancy was prolonged

from 5.3 years to 5.8 years when

immunosuppression was

continued

How to withdraw IS?

• No consensus, but…

• All IS drug can be withdrawn immeditely after

transplantectomy exept for steroids (consider

risk of adrenal insufficiency)

• Two approches to the weaning of IS:

– Stop antimetabolites at RRT initiation, taper CNI over

several weeks

– Stop CNI at RRT initiation taper antimetabolite

• In case of severe acute rejection start steroid

again and performe transplantectomy when

acute inflammation has settled

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Key messages about immunusuppresive

treatment withdrawal after failed KTx

• IS should be maintained only for patients with

living donor (or deceased?) transplantation

foreseen in the short term (<1 year)

• For all other cases weaning process must be

considered at various speed according to

individual situation (balance the risks and

benefits for each patient)

• Special situation: Multi-organ Tx: do not forget

the still functioning Tx (liver, pancreas, heart,...)

=> keep on monitoring IS

TRANSPLANTECTOMY

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Transplantectomy ?

PRO

• Increased mortality if

failed KTx is retained (?)

• Infection risk associated

with IS

• Cardiovascular risk

associated with IS

• Cancer risk associated

with IS

• Metabolic AE associated

with IS

• Removal of infection

source (chronic

pyelonephritis, BK-VAN)

CONS

• Residual kidney function

(especially in PD

patients)

• Risk of surgery (morbidity

17-60% and mortality 1,5-

14%)

• More immunization after

transplantectomy

“Transplant Nephrectomy Improves Survival

following a Failed Renal Allograft” Aysus et al JASN 2010

• USRDS 1994-2004

• 10.951 adults with failed

KTx

• 31% with transplantectomy

1,66 years post RRT

• Pts with transplantectomy:

– 4,6 years younger

– Less smokers

– Less often males

– Less MACE

– Less peripheral vascular

disease

– Less diabetes

– Less COPD

– Less cancer

Adj HR: 0,68 (0,63-0,74)

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Surgical techniques and complications

Extra-capsular Sub-capsular

• Preferred technique for

late nephrectomy

• More often complicated

with bleeding

• Leave more allograft

tissue in situ

(immunological trigger?)

• Mostly in the 3 first month

• Allow for almost complete

removal of the

transplanted tissue

• In rare selected cases

can be used later to allow

retransplantation in the

same site.

• Morbidity 17-60% (bleeding, sepsis, wound

infection, hematoma, lymphocele,…)

• Mortality: 1,5 to 14% (earlier post-Tx and

urgent indication being associated with the

worst outcome)

Transplantectomy: indications Absolute

• Primary non-function

• Hyper-acute rejection

• Early recalcitrant rejection

• Early graft lost (<1 year)

• Arterial or venous

thrombosis

• Graft intolerance syndrome

• Recurrent urinary tract

infection or sepsis

• Multiple retained failed

transplant before repeat

transplant

• Cancer

Relative

• Chronic inflammation

state:

– EPO resistant anemia

– Elevated ferritin level

– Elevated CRP

– Elevated erythrocyte

sedimentation rate

– Low (pre-)albumin

• Graft lost due to BKAN

with high level BK viremia

Pham et al, World J Nephrol 2015, pp 148-159

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On-going RCT

• Intervention: early (<2 month) transplantectomy under

immunosuppression vs progressive immunosuppression weaning

• Primary outcome: anti-HLA immunization (measured by Luminex test) a

year after graft-loss and return to dialysis in the renal transplant patient.

• Secondary outcome:

– Morbidity and mortality after transplantectomy

– Measuring the impact of systematic transplantectomy on mortality, inflammation,

nutritional status, anemia, hypertension and cardiovascular risk factor

– Infectious comorbidity

• Multi-center. N=118

INTEGRATED APPROACH

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Late allograft

Late allograft failure

Candidate Candidate for new

KTx

No Moderate to Moderate to severe IS

treatment AE

Yes Wean IS off Graft

intolerance

Yes Nx

No Keep KTx

No: reduce IS

HD Urine Urine

output>500 ml/d

Yes Keep KTx Keep KTx

and IS

No Wean off IS

PD Urine Urine

output>250 ml/d

Yes Keep KTx Keep KTx

and IS

No Wean off IS

Yes Living donor or Living donor or

KTx <1 year

Yes Keep IS

until KTx

No Moderate to Moderate to severe IS

treatment AE * Idem supra …*

*